JP7628405B2 - Composition for external use on skin, method for controlling skin permeability of anti-inflammatory or antibacterial ingredient, and method for reducing skin irritation caused by anti-inflammatory or antibacterial ingredient - Google Patents

Description

The present invention relates to a composition for topical application to the skin, a method for controlling the skin permeability of an anti-inflammatory or antibacterial ingredient, and a method for reducing skin irritation caused by an anti-inflammatory or antibacterial ingredient.

Antibacterial and anti-inflammatory agents are used as active ingredients in medicines and quasi-drugs and are incorporated into topical skin preparations to treat skin diseases and improve various skin conditions.

However, it has been reported that some patients and/or users may experience side effects due to the active ingredients of pharmaceuticals used to treat skin diseases, including steroid contact allergies, non-steroid contact allergies, antifungal agent contact allergies, antibiotic contact allergies, and allergic contact dermatitis (see Non-Patent Document 1).

It is also known that the incidence of contact dermatitis due to topical drugs is relatively higher in patients with atopic dermatitis (AD) than in non-AD patients (see Non-Patent Document 2). For this reason, if it were possible to control the permeability of active ingredients into the skin, it would be possible to reduce side effects such as dermatitis and skin irritation while maintaining the effectiveness of the topical composition, and therefore there has been a strong demand for technology to control the permeability of antibacterial agents and anti-inflammatory agents.

Addiction Research, Vol. 12, No. 3.Page. 275-282, 1999 Environmental Dermatology, Vol. 7, No. 3, Page 137-143, 2000

The present invention was made in consideration of such circumstances, and aims to provide a technology that can control the permeability of active ingredients of therapeutic pharmaceuticals, such as anti-inflammatory ingredients and antibacterial ingredients, into the skin. It is also an object of the present invention to provide a composition for external use on the skin that can control the permeability of the active ingredients into the skin.

As a result of intensive research conducted by the inventors to solve the above problems, they discovered that by incorporating a dicarboxylic acid having 3 to 10 carbon atoms and carboxyl groups at both ends into a composition for topical application to the skin, it is possible to control the permeability of active ingredients of therapeutic drugs, such as anti-inflammatory ingredients and antibacterial ingredients, into the skin. In other words, the gist of the present invention is as follows.

[1] A composition for external application to the skin, comprising (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends, and (B) at least one component selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2).
[2] The topical skin composition described in [1], wherein the dicarboxylic acid (A) has 4 to 9 carbon atoms.
[3] (b1) The composition for external use on skin according to [1] or [2], wherein the anti-inflammatory component is a non-steroidal anti-inflammatory analgesic component.
[4] (b2) A composition for external use on the skin described in any one of [1] to [3], wherein the antibacterial component is isopropyl methylphenol.
[5] The topical skin composition described in any one of [1] to [4], wherein the component (B) includes an anti-inflammatory component (b1) and an antibacterial component (b2).
[6] The topical skin composition described in any one of [1] to [5], wherein the dicarboxylic acid (A) is at least one selected from the group consisting of adipic acid, azelaic acid, tartaric acid, and succinic acid.
[7] A method for controlling the skin permeability of at least one component selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2) in a preparation, comprising using (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends.
[8] A method for reducing skin irritation caused by at least one component selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2) in a preparation, comprising using (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends.

The topical skin composition of the present invention contains (A) a dicarboxylic acid having 3 to 10 carbon atoms and carboxyl groups at both ends, which makes it possible to effectively control the permeability of at least one component (B) selected from the group consisting of anti-inflammatory and antibacterial components into deeper layers of the skin. Therefore, according to the present invention, it is possible to design a topical skin composition that can reduce dermatitis and skin irritation caused by the penetration of active ingredients such as the above-mentioned (B) component into deeper layers of the skin. In addition, by controlling the permeability, the active ingredient can be retained in the layer of the skin where it should exert its effect, and can exert its effect more effectively.

The present invention will be described in detail below. Note that the terms used in this specification are to be interpreted as having the meanings normally used in the relevant technical field unless otherwise specified.

<Composition for external use on skin>
The skin topical composition of the present invention contains (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends (also referred to simply as "(A) dicarboxylic acid" in this specification), and (B) at least one component selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2) (also referred to simply as "(B) component" in this specification). The skin topical composition of the present invention contains (A) dicarboxylic acid, which makes it possible to effectively control the permeability of the (B) component into deeper parts of the skin layer. Therefore, according to the present invention, it is possible to reduce or suppress dermatitis and skin irritation caused by the penetration of an active ingredient such as the (B) component into deeper parts of the skin layer. In addition, by controlling the permeability, the active ingredient can be retained in the skin layer where it is supposed to exert its effect, and can exert its effect more effectively.

The topical skin composition of the present invention may contain other ingredients in addition to the dicarboxylic acid (A) and the component (B) as long as the effects of the present invention are not impaired. The dicarboxylic acid (A) and the component (B), as well as the other ingredients, are described below.

[(A) Dicarboxylic acid]
The dicarboxylic acid (A) contained in the skin topical composition of the present invention is a compound having 3 to 10 carbon atoms and having carboxyl groups at both ends. Specific examples include malonic acid, succinic acid, tartaric acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid. Among these, from the viewpoint of excellent effect of controlling, and particularly inhibiting, the penetration of the component (B) described below into the deeper layers of the skin, a dicarboxylic acid having 4 to 9 carbon atoms is preferable, adipic acid and azelaic acid are more preferable, and adipic acid is even more preferable. The component (A) may contain one of the above components alone or two or more of them together.

The content of dicarboxylic acid (A) in the topical skin composition of the present invention is 0.001% by weight to 10% by weight, preferably 0.005% by weight to 5% by weight, more preferably 0.01% by weight to 1% by weight, and even more preferably 0.05% by weight to 0.5% by weight. By containing dicarboxylic acid (A) in the above numerical range, the topical skin composition of the present invention can effectively inhibit the penetration of component (B), described below, into the deeper layers of the skin.

[Component (B)]
The component (B) contained in the skin topical composition of the present invention is at least one component selected from the group consisting of anti-inflammatory components (b1) and antibacterial components (b2). These components, which are used as active ingredients in pharmaceuticals for treating skin diseases, may penetrate not only near the surface of the skin but also deeper into the dermis of the skin layer when used in a skin topical composition, and may cause side effects such as dermatitis and skin irritation. The skin topical composition of the present invention contains the above-mentioned dicarboxylic acid (A) together with these active ingredients, thereby controlling the permeability of the active ingredients into the skin, and reducing or suppressing side effects such as dermatitis and skin irritation while maintaining the action effect. In addition, by controlling the permeability, the active ingredients can be stored in the layer of the skin where they should exert their action effect, and can exert their action more effectively. Furthermore, it has been found that the inclusion of the dicarboxylic acid (A) not only effectively controls the permeability of the (B) component into the deeper layers of the skin layer, but also provides the unexpected effect of improving the stability of the (B) component.

The anti-inflammatory component (b1) is not particularly limited as long as it has an anti-inflammatory effect. Anti-inflammatory components are classified into steroidal anti-inflammatory components (SAIDs) and non-steroidal anti-inflammatory components (NSAIDs). In the present invention, however, non-steroidal anti-inflammatory components (non-steroidal anti-inflammatory analgesic components) are preferred from the viewpoint that the penetration control effect of the (A) dicarboxylic acid can be easily obtained.

In the present invention, examples of nonsteroidal anti-inflammatory analgesic ingredients include ibuprofen, ibuprofen piconol (IPPN), naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, sazapirin, sodium salicylate, aspirin, aspirin dialluminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinolyl, fenbufen, napumetone, proglumetacin, indomethacin farnesyl, acemetacin, maleic acid Proglumetacin, amfenac sodium, mofezolac, etodolac, mefenamic acid, aluminum mefenamate, tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, napagerun ointment, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, sulpyrine, migrenin, salidon, cedas G, amipiro-N, sorbon, pyridine cold medicines, acetaminophen, phenacetin, dimethothiazine mesylate, simetride combination drug, non-pyrine cold medicines, allantoin and its derivatives, glycyrrhetinic acid and its derivatives, glycyrrhizinic acid and its derivatives, salicylic acid derivatives, aminocaproic acid, azulene and its derivatives, zinc oxide, tocopherol acetate, etc.

Among these, from the viewpoint of the ease of obtaining the penetration control effect of the dicarboxylic acid (A), propionic acid-based anti-inflammatory agents such as ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, and zaltoprofen are preferred, and among these, ibuprofen piconol is more preferred.

The content of the anti-inflammatory component (b1) in the topical skin composition of the present invention is 0.01% by weight to 10% by weight, preferably 0.05% by weight to 8% by weight, more preferably 0.1% by weight to 5% by weight, and even more preferably 0.2% by weight to 3% by weight. If the topical skin composition contains the anti-inflammatory component (b1) in the above numerical range, it will penetrate deeper into the dermis of the skin layer and may cause various side effects. However, by including the above-mentioned (A) component, the penetration of the (b1) component can be controlled, and side effects can be reduced or suppressed.

The antibacterial component (b2) is not particularly limited as long as it has the effect of inhibiting the growth of various bacteria and has a bactericidal effect, and examples thereof include isopropylmethylphenol (IPMP), salicylic acid, benzoic acid, amorolfine, chlorhexidine and their salts, benzalkonium chloride, acrinol, ethanol, benzethonium chloride, cresol, gluconic acid and its derivatives, povidone-iodine, potassium iodide, iodine, triclocarban, triclosan, photosensitizer No. 101, photosensitizer No. 201, phenoxyethanol, alkyldiaminoglycine hydrochloride, etc.

Of these, isopropylmethylphenol and salts thereof are preferred as component (b2) from the viewpoint that the penetration control effect of the dicarboxylic acid (A) can be easily obtained, with isopropylmethylphenol, salicylic acid, and benzoic acid being more preferred, and isopropylmethylphenol being even more preferred.

The content of the (b2) component in the topical skin composition of the present invention is 0.005% by weight to 10% by weight, preferably 0.01% by weight to 8% by weight, more preferably 0.05% by weight to 5% by weight, even more preferably 0.1% by weight to 3% by weight, and particularly preferably 0.3% by weight to 1% by weight. If the topical skin composition contains the antibacterial component (b2) in the above numerical range, it may penetrate deeper into the dermis of the skin layer and cause various side effects, but by including the above-mentioned (A) component, the penetration of the (b2) component can be controlled, and side effects can be reduced or suppressed.

From the viewpoint that the permeation control effect of the component (A) is significant, the composition for topical use on the skin of the present invention preferably contains at least the component (b1) as the component (B), and more preferably contains both the components (b1) and (b2). The inventors did not expect that the permeation control effect of the dicarboxylic acid (A) into the skin would be more significant when the component (B) contains both components, compared to when either the component (b1) or the component (b2) is contained alone.

The total content of the (B) component in the skin topical composition of the present invention is 0.005% to 20% by weight, preferably 0.01% to 15% by weight, more preferably 0.05% to 10% by weight, even more preferably 0.1% to 8% by weight, particularly preferably 0.5% to 6% by weight, particularly more preferably 1% to 5% by weight, and most preferably 2.0% to 4.0% by weight. When the skin topical composition contains the (B) component in the above numerical range, it penetrates deeper into the dermis of the skin layer and may cause various side effects, but by including the above-mentioned (A) component, the penetration of the (B) component is significantly controlled, and side effects can be reduced or suppressed. In addition, the penetration of the (B) component is controlled and it is stored in the upper part of the skin layer, so that the effect can be more effectively achieved.

In the topical skin composition of the present invention, the ratio of the content of dicarboxylic acid (A) to component (B) is 0.0001 to 10 parts by weight, preferably 0.001 to 5 parts by weight, more preferably 0.005 to 1 part by weight, even more preferably 0.01 to 0.5 parts by weight, and particularly preferably 0.025 to 0.1 parts by weight, of dicarboxylic acid (A) per 1 part by weight of component (B). By containing dicarboxylic acid (A) and component (B) in the above ratio in the topical skin composition of the present invention, component (B) can penetrate deeper into the dermis of the skin layer, effectively suppressing the occurrence of various side effects.

In the topical skin composition of the present invention, the ratio of the content of dicarboxylic acid (A) to component (b1) is 0.0002 to 5 parts by weight, preferably 0.001 to 4 parts by weight, more preferably 0.002 to 2 parts by weight, and even more preferably 0.01 to 2 parts by weight, of dicarboxylic acid (A) per 1 part by weight of component (b1). By containing dicarboxylic acid (A) and component (b1) in the above ratio, the topical skin composition of the present invention can effectively prevent component (b1) from penetrating deeper into the dermis of the skin layer and causing various side effects.

In the skin topical composition of the present invention, the ratio of the content of the dicarboxylic acid (A) to the component (b2) is 0.001 to 200 parts by weight, preferably 0.005 to 100 parts by weight, more preferably 0.01 to 20 parts by weight, even more preferably 0.05 to 10 parts by weight, and particularly preferably 0.1 to 0.5 parts by weight, of the dicarboxylic acid (A) per 1 part by weight of the component (b2). By containing the dicarboxylic acid (A) and the component (b2) in the above ratio in the skin topical composition of the present invention, the component (b2) can penetrate deeper into the dermis of the skin layer, effectively suppressing the occurrence of various side effects.

[(C) Chelating Agent]
The composition for external use on the skin of the present invention preferably further contains a chelating agent (C). By further containing a chelating agent (C), the composition for external use on the skin of the present invention can more effectively control the skin penetration of the component (B).

(C) Examples of chelating agents include EDTA, hydroxyethanediphosphonic acid, citric acid, and salts thereof. More specifically, examples include EDTA (EDTA-2Na salt, EDTA-4Na salt), calcium disodium hydroxyethanediphosphonic acid, and the like. Of these, EDTA and its salts are preferred from the viewpoint of further enhancing the effects of the present invention.

The content of the chelating agent (C) in the topical skin composition of the present invention is 0.001% to 1% by weight of the entire topical skin composition, preferably 0.005% to 0.5% by weight, and more preferably 0.01% to 0.1% by weight. By including the chelating agent (C) in the above range, the skin penetration of the component (B) can be more effectively controlled.

(D) Lipids
The topical composition for skin of the present invention preferably further contains a lipid (D). By further containing a lipid (D), the topical composition for skin of the present invention can effectively control the skin penetration of the component (B).

(D) Examples of lipids include phospholipids, cholesterol, ceramide, etc. Among these, from the viewpoint of further enhancing the effects of the present invention, phospholipids are preferred, and among these, lecithin and hydrogenated lecithin are more preferred.

The content of the lipid (D) in the topical skin composition of the present invention is 0.001% to 8% by weight of the entire topical skin composition, preferably 0.01% to 5% by weight, more preferably 0.05% to 3% by weight, and even more preferably 0.1% to 2% by weight. By including the lipid (D) in the above numerical range, the penetration of the component (B) into the skin can be more effectively controlled.

The topical skin composition of the present invention may contain other optional ingredients, bases or carriers, additives, etc., in addition to the above-mentioned ingredients (A) to (D), as long as the effects of the present invention are not impaired.

[Optional ingredients]
Examples of optional components contained in the topical skin composition of the present invention include whitening components, turnover promoters, anti-glycation components, antioxidant components, anti-aging components, anti-inflammatory agents other than component (b1), cooling agents, vitamins, organic acids other than (A) dicarboxylic acid, moisturizing components, polyhydric alcohols, emulsifiers, scrubbing agents, UV absorbing components, UV scattering components, astringent components, peptides or derivatives thereof, amino acids or derivatives thereof, cleansing components, keratin softening components, cell activating components, blood circulation promoting components, etc. In the topical skin composition of the present invention, each of these components may be used alone or in combination of two or more.

Examples of the whitening ingredients include tocopherol, vitamin C and its derivatives, arbutin, kojic acid, placenta extract, ellagic acid, nicotinamide, tranexamic acid and its derivatives, hydroquinone, 4-n-butylresorcinol, potassium 4-methoxysalicylic acid, linoleic acid and its derivatives, etc.

Examples of the turnover promoter include vitamins, keratin softening ingredients, cell activation ingredients, blood circulation promoting ingredients, etc., which are described below.

The above-mentioned anti-glycation ingredients include, for example, plant extracts such as Budreja axillaris leaf extract, evening primrose oil, amla fruit, fruit juice or extracts thereof, L-arginine, L-lysine, hydrolyzed casein, hydrolyzable tannin, carnosine, etc.

The above antioxidant components include, for example, components derived from plants (e.g., grapes, ginseng, comfrey, etc.); proanthocyanidin, tocopherol and its derivatives, ascorbic acid and its derivatives, hesperidin and its derivatives, ergothioneine, sodium bisulfite, erythorbic acid and its salts, flavonoids, glutathione, etc.

Examples of the anti-aging ingredients include hydrolyzed soy protein, retinoids (retinol and its derivatives, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone, etc.

The above-mentioned cooling agents include, for example, terpenes such as menthol, camphor, geraniol, etc. (which may be in the d-, l- or dl-form); essential oils such as eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, and peppermint oil; and the like.

The vitamins may be either water-soluble or oil-soluble, and examples thereof include vitamin B6, pantothenic acid, nicotinic acid, vitamin B1, vitamin B2, biotin, folic acid, vitamin B12, water-soluble vitamin C, oil-soluble vitamin C, vitamin K; and vitamin-like factors such as ferulic acid.

Examples of the organic acids other than the dicarboxylic acids (A) include gluconic acid, aspartic acid, aminoethylsulfonic acid, citric acid, glutamic acid, oxalic acid, fumaric acid, propionic acid, malic acid, salicylic acid, glycolic acid, phytic acid, acetic acid, lactic acid, and salts thereof. Examples of the salts include salts of mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, salts of organic acids such as maleic acid and methanesulfonic acid, alkali metal salts such as sodium and potassium, alkaline earth metal salts, and ammonium salts.

Examples of the moisturizing ingredients include polymeric compounds such as sodium hyaluronate, heparinoids, sodium chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan, and proteoglycan; amino acids such as glycine, aspartic acid, and arginine; natural moisturizing factors such as sodium lactate, urea, and sodium pyrrolidone carboxylate; plant extracts such as chamomile extract, witch hazel extract, tea extract, and perilla extract; and polyhydric alcohols such as glycerin.

The polyhydric alcohol preferably has 2 to 10 carbon atoms, and examples thereof include glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1,3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol, decanediol, and neopentyl glycol.

Examples of the emulsifiers include polyether-based silicones such as polyether-modified silicones and crosslinked polyether-modified silicones; polyoxyethylene hydrogenated castor oils such as POE (5), POE (7.5), and POE (10) hydrogenated castor oils; dipolyhydroxystearic acid esters: high molecular weight lipophilic surfactants such as polyglyceryl-2 dipolyhydroxystearate and PEG 30 dipolyhydroxystearate; cetyl dimethicone copolyol, etc.

Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride granules, olive kernel powder, seawater dried granules, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, charcoal powder, hazel shell powder, polyethylene powder, anhydrous silicic acid, etc.

Examples of the ultraviolet absorbing components include ethylhexyl methoxycinnamate, diethylamino hydroxybenzoyl hexyl benzoate, bisethylhexyloxyphenol methoxyphenyl triazine, ethylhexyl triazone, t-butyl methoxydibenzoylmethane, octocrylene, ethylhexyl salicylate, homosalate, polysilicone-15, methylene bisbenzotriazolyl tetramethylbutylphenol, dimethoxybenzylidene dioxoimidazolidine octyl propionate, and phenylbenzimidazole sulfonic acid.

Examples of the ultraviolet scattering components include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, iron oxide, zinc oxide, and anhydrous silicic acid, and these inorganic compounds are coated with inorganic powders such as hydrous silicic acid, aluminum hydroxide, mica, and talc, or are composited with resin powders such as polyamide, polyethylene, polyester, polystyrene, and nylon, and further treated with silicone oil, aluminum salt of fatty acid, etc.

Examples of the astringent ingredients include alum, zinc sulfate, aluminum chloride, zinc sulfocarbonate, tannic acid, etc.

Examples of the above peptides or derivatives thereof include keratin hydrolyzed peptides, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin hydrolyzed peptides, collagen hydrolyzed peptides, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, elastin hydrolyzed peptides, conchiolin hydrolyzed peptides, hydrolyzed conchiolin, silk proteolytic peptides, hydrolyzed silk, sodium lauroyl hydrolyzed silk, soybean proteolytic peptides, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptides, hydrolyzed wheat protein, casein hydrolyzed peptides, acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.), etc.

Examples of the above amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine, methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine, etc.

Examples of the cleaning components include soaps selected from alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate, and potassium stearate, alkanolamide salts, and amino acid salts; amino acid surfactants such as sodium cocoyl glutamate and sodium cocoyl methyl taurate; ether sulfate ester salts such as sodium laureth sulfate; ether carboxylates such as sodium lauryl ether acetate; sulfosuccinate ester salts such as sodium alkyl sulfosuccinate; fatty acid alkanolamides such as coconut oil fatty acid monoethanolamide and coconut oil fatty acid diethanolamide; monoalkyl phosphate ester salts such as sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate; betaine-type amphoteric surfactants such as coconut oil fatty acid amidopropyl dimethylaminoacetate betaine, lauryl dimethylaminoacetate betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, lauryl hydroxysulfobetaine, and sodium lauroyl amidoethyl hydroxyethyl carboxymethyl betaine hydroxypropyl phosphate; and amino acid amphoteric surfactants such as sodium lauryl aminopropionate.

Examples of the above-mentioned keratin softening ingredients include lactic acid, salicylic acid, glycolic acid, citric acid, malic acid, fruit acid, phytic acid, urea, sulfur, etc.

The above-mentioned cell activation components include, for example, amino acids such as γ-aminobutyric acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponin, photosensitizer No. 301, etc.

The above blood circulation promoting ingredients include ingredients derived from plants (e.g., ginseng, angelica, arnica, ginkgo, fennel, Japanese oak, Dutch oak, chamomile, Roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake mushroom, ginger, European hawthorn, European juniper, cnidium rhizome, Swertia japonica, thyme, clove, tangerine peel, red pepper, angelica tree, tonin, spruce, carrot, garlic, butcher's broom, grape, peony, horse chestnut, melissa, yuzu, coix seed, ryokucha, rosemary, rose hip, tangerine peel, angelica tree, spruce, peach, apricot, walnut, corn, etc.); acetylcholine, ichthammol, cantharides tincture, gamma oryzanol, cepharanthine, tolazoline, tocopherol nicotinate, glucosyl hesperidin, etc.

[Substrate or carrier]
Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, petrolatum, gelling hydrocarbons (such as Plastibase), ozokerite, α-olefin oligomers, and light liquid paraffin; silicone oils such as methylpolysiloxane, cyclic silicone, modified silicone, and silicone resin; oils and fats such as coconut oil, olive oil, rice bran oil, and shea butter; waxes such as jojoba oil, meu wax, candelilla wax, and lanolin; cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, and phytosterol. higher alcohols such as methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, carrageenan, polyethylene glycol, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythritol tetra 2-ethylhexanoate and other esters; polysaccharides such as dextrin and maltodextrin; lower alcohols such as ethanol; glycol ethers such as diethylene glycol monoethyl ether; and water.

The bases or carriers described above may be used alone or in combination of two or more. The amounts used may be appropriately selected from the ranges known to those skilled in the art.

[Additives]
The skin topical composition of the present invention may contain known additives added to pharmaceuticals and quasi-drugs, such as surfactants, antioxidants, colorants, pearlescent agents, pH adjusters, preservatives, thickeners, etc., within the scope of not impairing the effects of the present invention. These additives may be used alone or in combination of two or more.

The surfactant may be any of nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants, etc., and examples thereof include sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexyl acid, and diglycerol sorbitan tetra-2-ethylhexyl acid; propylene glycol fatty acid esters such as propylene glycol monostearate; hydrogenated castor oil derivatives such as polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80; polyoxyethylene monolaurate, Examples of such surfactants include polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monostearate (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyethylene (20) sorbitan isostearate; polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ethers; alkyl glucosides; polyoxyalkylene alkyl ethers such as polyoxyethylene cetyl ether; amines such as stearylamine and oleylamine; silicone surfactants such as polyoxyethylene-methylpolysiloxane copolymers, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone.

Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, and L-cysteine hydrochloride.

Examples of the coloring agents include inorganic pigments, natural dyes, etc.

Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, etc.), inorganic bases (potassium hydroxide, sodium hydroxide, etc.), and organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

Examples of the preservatives include dehydroacetic acid, sodium dehydroacetate, phenoxyethanol, caprylhydroxamic acid, and alkanediols such as pentanediol, hexanediol, and octanediol.

Examples of the thickening agents include vinyl thickening agents such as polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers; cellulose thickening agents such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxyethylcellulose; guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, xanthan gum, acrylates/alkyl methacrylate copolymers, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, sodium chondroitin sulfate, hyaluronic acid, sodium hyaluronate, (hydroxyethyl acrylate/Na acryloyldimethyltaurate) copolymer, (ammonium acryloyldimethyltaurate/vinylpyrrolidone) copolymer, and the like.

[Method of manufacturing the composition for external use on skin]
The method for producing the topical skin composition of the present invention is not particularly limited, and the composition can be produced by a conventional method by appropriately selecting and mixing the essential components (A) dicarboxylic acid, component (B), and other components (optional components, base or carrier, additives, etc.) that are mixed as necessary.

[Uses of topical skin composition]
The composition for external use on the skin of the present invention may be used as a medicine or quasi-drug having at least one of its therapeutic effects such as anti-inflammatory or antibacterial effects.

[Dosage Form]
The formulation of the skin topical composition of the present invention is not particularly limited, and examples thereof include liquids, creams, gels, jelly, sherbet, aerosols, foams, sprays, patches, sticks, ointments, solids, etc. These preparations can be manufactured according to conventional methods, such as the methods described in the General Provisions of Preparations in the 17th Revised Japanese Pharmacopoeia. In addition, taking into consideration the desired stability, usability, etc., dosage forms such as W/O, O/W, W/O/W, and O/W/O type emulsions can be appropriately selected. The patch may be, for example, a nonwoven fabric sheet, gel sheet, etc. impregnated with a beauty essence composition, a lotion composition, an emulsion composition, etc.

[pH]
The pH of the composition for external use on skin of the present invention is usually pH 3.0 to 8.0, preferably pH 3.5 to 7.5, more preferably pH 4.0 to 6.8, even more preferably pH 4.5 to 6.5, and particularly preferably pH 5.0 to 6.0. The pH can be adjusted, for example, by using a pH adjuster. However, this does not apply to formulations in which pH measurement is impossible or difficult.

The administration or application method of the topical skin composition of the present invention can be transdermal administration, but a suitable method can be selected depending on the type of disease and the purpose of use.

The skin topical composition of the present invention has the effect of reducing skin irritation by controlling the skin permeability, and therefore can be used for sensitive skin and rough skin. Sensitive skin refers to a skin quality in which, even though there is no obvious inflammation or damage to the skin, the barrier function of the keratin is weakened and the skin is susceptible to tingling pain or burning sensation due to stimuli from the external environment (chemical substances, hair, fibers of clothing, etc.). In sensitive skin, the amount of intercellular lipids between the keratin is less than that of healthy skin, and as a result, the skin texture is disturbed, the barrier function is weakened, and the irritation threshold is lowered, making the skin more susceptible to irritation. Therefore, the skin topical composition of the present invention can be suitably used to improve the skin quality of sensitive skin. Rough skin also includes skin with a disturbed skin texture, i.e., skin with a broken barrier function, and sensitive skin in which the barrier function is easily broken.

<Method of controlling skin permeability of component (B)>
The present invention also includes a method for controlling the skin permeability of at least one component selected from the group consisting of (B) an anti-inflammatory component (b1) and an antibacterial component (b2) in a preparation, which is characterized by using (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends. The present inventors have found for the first time that in a skin topical composition containing the above-mentioned (b1) and/or (b2) components as active ingredients, the penetration of the above-mentioned (b1) and/or (b2) components into deeper layers of the skin layer can be effectively controlled by blending the above-mentioned (A) dicarboxylic acid together. This new technology makes it possible to reduce and suppress dermatitis and skin irritation that may be caused by the penetration of active ingredients such as the above-mentioned (B) component into deeper layers of the skin layer. The above-mentioned skin topical composition is a preparation that realizes this technology. Note that the specific explanation of the (A) dicarboxylic acid, the (B) component, etc. in the method of the present invention can be applied as it is to the explanation in the section on the skin topical composition.

<Method for reducing skin irritation caused by component (B)>
The present invention also includes a method for reducing skin irritation caused by at least one component selected from the group consisting of (B) anti-inflammatory component (b1) and antibacterial component (b2) in a preparation, which is characterized by using (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends. In a skin topical composition containing the above-mentioned (b1) component and/or (b2) component as an active ingredient, by blending (A) dicarboxylic acid together, it is possible to effectively control the penetration of the above-mentioned (b1) component and/or (b2) component into deeper parts of the skin layer, as described above. This technology of the present invention makes it possible to reduce and suppress dermatitis and skin irritation that may be caused by the penetration of an active ingredient such as the above-mentioned (B) component into deeper parts of the skin layer. Therefore, the present invention can also be said to be a method for reducing skin irritation caused by the (B) component, which is characterized by using (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends. Note that the explanation in the section on skin topical composition can be applied as it is to the specific explanation of the (A) dicarboxylic acid, the (B) component, etc. in the method of the present invention.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

<Skin penetration test>
In this test, the permeability of the active ingredient was calculated by conducting a test in accordance with the OECD TG428 (Skin Absorption: In Vitro Method, adopted on April 13, 2004), which is an in vitro skin absorption test method, in accordance with the guidelines for testing of chemical substances set by the Organization for Economic Cooperation and Development (OECD).

More specifically, each composition was prepared by a conventional method according to the composition in Table 1, and the permeability of each component in the composition was confirmed by measuring it in an infinite closed system using a Franz cell (PermeGear, jacketed stationary type - flat jacket - clear - 9 mm, 5 mL, permeation area 0.64 cm2). That is, a reservoir solution (0.1% (w/v) polyethylene glycol monooleyl ether (20 E.O.) in PBS) was prepared, and 5 mL of the reservoir solution was filled into the receptor chamber and stirred for 30 minutes. A piece of skin (pigskin (Yucatan Micro)) was placed between the Franz cell and a ground glass donor. Pig, about 700 μm) was sandwiched and fixed. The thermostatic bath was set to 32°C, and the thermostatic bath and the Franz cell were connected so that the reservoir solution was kept at a constant temperature. 24 hours after the start of stirring, the Franz cell was disassembled, the skin pieces were removed, the reservoir solution was collected, and the content of each component in the reservoir solution was measured by HPLC. Each component was detected using an ultraviolet absorption spectrophotometer at a wavelength of 280 nm, and the content (rate) was calculated from the calibration curve of each component. The permeability inhibition rate for each composition was calculated according to the following formula (1). In the following formula, "corresponding comparative example" refers to the comparative example with the same number as the example, for example, the comparative example corresponding to Example 1 is Comparative Example 1. The test results are also shown in Table 1.

Permeation inhibition rate (%)=(1−permeation amount of the example/permeation amount of the corresponding comparative example)×100
...(1)

As shown in Table 1 above, in the skin topical compositions containing the active ingredients isopropyl methylphenol and/or ibuprofen piconol, it was confirmed that the penetration of both isopropyl methylphenol and ibuprofen piconol deeper than the dermis was suppressed in the examples containing adipic acid compared to the comparative examples not containing adipic acid. In other words, in the skin topical compositions of Comparative Examples 1 and 2 not containing adipic acid, when applied to the skin, the active ingredients contained in each of them penetrate the epidermis and dermis and penetrate deeper, whereas in the skin topical compositions of Examples 1 and 2 containing adipic acid, the penetration of the active ingredients to the deeper layers as described above was significantly suppressed. Interestingly, it was found that the penetration suppression rate of the active ingredients was significantly higher in Example 2 containing two types of the above active ingredients than in Example 1 containing only ibuprofen piconol. Furthermore, it was confirmed that the penetration suppression rate of the active ingredients was significantly increased when the chelating agent EDTA or the lipid lecithin was added (Examples 3 and 4).

In addition, a cream formulation (Example 5, pH 5.6) containing 3% ibuprofen piconol, 0.1% adipic acid, 1,3-butylene glycol, isopropyl palmitate, diethyl sebacate, polyoxyethylene hydrogenated castor oil, ethanol, glycerin, sorbitan stearate, squalane, carboxyvinyl polymer, soybean lecithin, cholesterol, sodium edetate, pH adjuster, and preservative, and a cream formulation (Comparative Example 5, pH 5.6) of the same formulation as Example 5 except that it does not contain 0.1% adipic acid were prepared, filled into a tube container with an innermost layer made of polyethylene, and stored at 40°C for 2 months under light-shielded conditions. In the cream formulation of Example 5, the stability of ibuprofen piconol tended to be improved compared to Comparative Example 5. It was found that the inclusion of adipic acid not only effectively controlled the penetration of ibuprofen piconol into deeper layers of the skin layer, but also provided the unexpected effect of improving the stability of ibuprofen piconol.

The following are examples of formulations (formulation examples) of the topical skin composition of the present invention. All of the following can be prepared by conventional methods. However, the present invention is not limited to these formulation examples.

According to the topical skin composition of the present invention, by containing (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends, it is possible to effectively control the penetration of at least one component (B) selected from the group consisting of anti-inflammatory components and antibacterial components into deeper parts of the skin layer. Therefore, according to the present invention, it is possible to design a topical skin composition that can reduce dermatitis and skin irritation caused by the penetration of active ingredients such as the above-mentioned component (B) into deeper parts of the skin layer. In addition, by storing the component (B) in the upper part of the skin layer, it is possible to design a topical skin composition with improved effectiveness.

Claims (2)

A composition for external use on the skin, comprising: (A) a dicarboxylic acid having 3 to 10 carbon atoms and having carboxyl groups at both ends; and (B) at least one component selected from the group consisting of an anti-inflammatory component (b1) and an antibacterial component (b2) ,
(A) the dicarboxylic acid is adipic acid, the anti-inflammatory component (b1) is ibuprofen piconol, and the antibacterial component (b2) is isopropyl methylphenol;
When the composition for external use on the skin contains isopropyl methylphenol as the antibacterial component (b2), the content of the isopropyl methylphenol in the composition for external use on the skin is 0.3% by weight to 1% by weight based on the total weight of the composition (excluding those containing polyoxyethylene polyoxypropylene decyl tetradecyl ether) . The topical skin composition according to claim 1 , wherein the component (B) comprises ibuprofen piconol as an anti-inflammatory component (b1) and isopropyl methylphenol as an antibacterial component (b2).